Nano & Microparticle Drug Delivery: How will it play a role in peripheral arterial interventions Subhash Banerjee, MD Associate Prof. of Medicine UT Southwestern Med. Ctr. Nov. 2013

Drug Coated Balloon (DCB) for Peripheral Arterial Interventions Success of DCB relies on the rapid transfer of a single dose of an anti-proliferative agent into the vessel wall The dominant challenge for DCB is rapid, uniform, efficient, & directed transfer of the drug to the vessel wall during balloon inflation with limited downstream distribution Tissue delivery=8.8±3.9% of the mean percentage of total original catheter load Cremers et al. Thromb Haemost. 2009; 101: 201–206

Drug Concentration of Current DCB Drug-Coated Balloon Manufacturer Drug Carrier Drug Dose Density (µg/mm²) Cotavance MEDRAD Paccocath Paclitaxel 3 SeQuent Please B. Braun Melsungen AG IN. PACT Medtronic-Invatec FreePac 3.5 Dior, Freeway Eurocor Shellac Moxy Lutonix-Bard Nonpolymeric 2 Pantera Lux Biotronik Butyryl-tri-hexyl citrate AngioSculpt AngioScore unkonwn Protege Blue Medical unknown Elutax Aachen Resonance No (2 layers of paclitaxel) Wombat Avidal Vascular No (paclitaxel wrapped) 3.3 Magic Touch Concept Medical Phospholipid based excipient Sirolimus 1.2 DCB 6x60 mm; 1 inflation=3391µg Paclitaxel coated balloon= Low-dose (0.2 μg/stent) Intermediate-dose (15 μg/stent) High-dose (187 μg/stent) Heldman et al. Circulation. 2001; 103: 2289-2295 Increased dose Balloon surface modifications that increase surface area and retention (contrast, fatty acids, urea) Paclitaxel: binding to the β subunit of tubulin, resulting in arrest of microtubule function. Paclitaxel is also characterized by prolonged tissue retention rates 4. 1130 sq mm; 3391 microgm; 6782.4 microgm Waxman et al. JACC Cardiovasc Interv.2012; 5:1001-12

Multi-Ligand Nanoparticles (MLNP) Paclitaxel “Platelet mimicking” Poly (L-lactic-co-glycolic acid) (PLGA) Surface conjugated ligands: polyethylene glycol (PEG) glycoprotein 1b (GP1b) trans-activating transcriptional peptide (TAT) Extensive biocompatibility testing Banerjee et al. J Cardiovasc Transl Res. 2013 Aug;6(4):570-8

MLNP Uptake by Injured Endothelial Cells (EC) Under flow conditions EC delivery PLGA-PEG PLGA-PEG-Gp1b PLGA-PEG-Gp1b/TAT Banerjee et al. J Cardiovasc Transl Res. 2013 Aug;6(4):570-8

Drug Delivering MLNP Coated Balloon Fluorescent Image of Nanoparticle-coated Angioplasty Balloon Tip Surface SEM of Nanoparticle-coated Angioplasty Balloon Uncoated angioplasty balloon surface Nanoparticle-coated balloon surface before inflation Nanoparticle-coated balloon surface after inflation/deflation Xu Hao et al. TCT 2013

Transfer of MLNP Coated Angioplasty Balloon to Rat Artery Angioplasty balloon without coating of nanoparticles Angioplasty balloon coated with nanoparticles before inflation Angioplasty balloon coated with nanoparticles after inflation-deflation Rat carotid artery before angioplasty Rat carotid artery after angioplasty 27% particles were lost 7% particles were transferred to the artery wall Banerjee et al. J Cardiovasc Transl Res. 2012 Aug;5(4):519-27

Paciltaxel-Loaded MLNP Suppresses Rat Carotid Artery Neointima Rat Carotid Balloon Injury Model Uninjured Normal saline Nanoparticles w/o paclitaxel Paclitaxel solution Paclitaxel-loaded nanoparticle Banerjee et al. J Cardiovasc Transl Res. (in submission)

Paciltaxel-Loaded MLNP Suppresses Rat Carotid Artery Neointima Rat Carotid Balloon Injury Model Banerjee et al. J Cardiovasc Transl Res. (in submission)

Drug Concentration of DCB

MLNP Loaded DCB for Peripheral Arterial Interventions Paclitaxel containing biodegradable, MLNP can be loaded on angioplasty balloons & delivered reliably to injured vascular surfaces with demonstrable suppression of neointimal proliferation MLNP-DCB may potentially offer a pathway for targeted drug delivery to injured vascular wall, at significantly reduced doses Future studies to refine the technology, assess comparative efficacy & safety are on-going